A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Doddapaneni, Bhuvana Shyam; Kyryachenko, Sergiy; Chagani, Sharmeen; Alany, Raid G.; Rao, Deepa; Indra, Arup K.; Alani, Adam W.G.

doi:10.1016/j.jconrel.2015.11.013

Cited by 21 publications

(14 citation statements)

References 54 publications

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“…Although mitogen-activated protein kinase pathway inhibitors and immunotherapies against the immune checkpoints cytotoxic T lymphocyte-associated antigen and programmed death 1 have largely replaced classical alkylating and cytostatic chemotherapeutics as first-line treatment [20, 22], the mitotic inhibitor paclitaxel and its derivative docetaxel [49] are being considered as adjuvant treatments [19, 21, 22] and explored for use in novel formulations (see e.g. [34, 35, 50, 51]). Given that our model in its current version lacks immune cells, immunotherapies were not in the focus of this study.…”

Section: Discussionmentioning

confidence: 99%

A novel spheroid-based co-culture model mimics loss of keratinocyte differentiation, melanoma cell invasion, and drug-induced selection of ABCB5-expressing cells

Klicks

Maßlo

Kluth³

et al. 2019

BMC Cancer

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Background Different 3D-cell culture approaches with varying degrees of complexity have been developed to serve as melanoma models for drug testing or mechanistic studies. While these 3D-culture initiatives are already often superior to classical 2D approaches, they are either composed of only melanoma cells or they are so complex that the behavior of individual cell types is hard to understand, and often they are difficult to establish and expensive. Methods This study used low-attachment based generation of spheroids composed of up to three cell types. Characterization of cells and spheroids involved cryosectioning, immunofluorescence, FACS, and quantitative analyses. Statistical evaluation used one-way ANOVA with post-hoc Tukey test or Student’s t-test. Results The tri-culture model allowed to track cellular behavior in a cell-type specific manner and recapitulated different characteristics of early melanoma stages. Cells arranged into a collagen-IV rich fibroblast core, a ring of keratinocytes, and groups of highly proliferating melanoma cells on the outside. Regularly, some melanoma cells were also found to invade the fibroblast core. In the absence of melanoma cells, the keratinocyte ring stratified into central basal-like and peripheral, more differentiated cells. Conversely, keratinocyte differentiation was clearly reduced upon addition of melanoma cells. Treatment with the cytostatic drug, docetaxel, restored keratinocyte differentiation and induced apoptosis of external melanoma cells. Remaining intact external melanoma cells showed a significantly increased amount of ABCB5-immunoreactivity. Conclusions In the present work, a novel, simple spheroid-based melanoma tri-culture model composed of fibroblasts, keratinocytes, and melanoma cells was described. This model mimicked features observed in early melanoma stages, including loss of keratinocyte differentiation, melanoma cell invasion, and drug-induced increase of ABCB5 expression in external melanoma cells. Electronic supplementary material The online version of this article (10.1186/s12885-019-5606-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A novel spheroid-based co-culture model mimics loss of keratinocyte differentiation, melanoma cell invasion, and drug-induced selection of ABCB5-expressing cells

Klicks

Maßlo

Kluth³

et al. 2019

BMC Cancer

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“…Transport by dendritic cells is more likely to occur when materials are large (>70 kDa or >50 nm), have too much of a negative charge or positive charge (<-47 mV or >56 mV demonstrated by Lunov et al), or are hydrophobic, as they are restricted to the injection site and may have problems moving though interstitial water channels [107,[121][122][123]. When substances are taken up by dendritic cells, they may not be able to exert their pharmacological effect against their target within the lymphatics [124]. Similar to subcutaneously administered medications, substances given intradermally can drain through lymphatic capillaries located in the dermal space and reach the lymph nodes [125,126].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Another study by Doddapaneni et al loaded nanoparticles made from different ratios of methoxy poly(ethylene glycol) 5,000 -block-poly(ε-caprolactone) 10,000 (mPEG-PCL) and carboxy poly(ethylene glycol) 5,000 -block-poly(ε-caprolactone) 10,000 (cPEG-PCL) [124]. mPEG-PCL nanoparticles alone had a charge of -6 mV, cPEG-PCL nanoparticles alone had a charge of -36 mV, and a 60:40 ratio of mPEG-PCL:cPEG:PCL had a charge of -19 mV.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Polymeric nanoparticles are made out of block co-polymers with hydrophobic and hydrophilic properties, and hydrophobic drugs can be loaded into the hydrophobic nanoparticle core [143]. A study by Doddapeneni et al shows that drug loaded PEG-PCL nanoparticles are able to passively target the lymphatic metastases after subcutaneous administration proximal to the site of the tumor [124]. Another nanoparticle prepared for lymphatic uptake is composed of methoxypoly(ethylene glycol)-b-poly(D L -lactic acid) (mPEG-PLA) and mixed poly(D Llactic-co-glycolic acid) (PLGA/mPEG-PLA) [148].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

Cote

Rao

Alany

et al. 2019

Advanced Drug Delivery Reviews

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Although many solid tumors use the lymphatic system to metastasize, there are few treatment options that directly target cancer present in the lymphatic system, and those that do are highly invasive, uncomfortable, and/or have limitations. This review gives a brief overview of lymphatic function and anatomy, discusses changes that befall the lymphatics in cancer and the mechanisms by which these changes occur, and presents limitations for drug delivery to the lymphatic system. We then go on to summarize relevant techniques and new research for targeting cancer populations in the lymphatics and enhancing drug delivery intralymphatically, including intralymphatic injections, isolated limb perfusion, passive nano drug delivery systems, and actively targeted nanomedicine.

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“…Formulating rapalogues for systemic delivery free of adverse effects remains a challenge 12 , 16 - 18 . To address these challenges, multiple materials have been proposed as advanced drug carriers in cancer models such as poly(lactide-co-glycolide) nanoparticles 34 , polyethyleneglycol- block -poly(ɛ-caprolactone) nanoparticles 35 , albumin-bound nanoparticles 36 and multi-drug loaded 'triolimus' micelles 37 . Compared to these formulations, the carriers evaluated in this manuscript differ in two fundamental ways.…”

Section: Introductionmentioning

confidence: 99%

Berunda Polypeptides: Multi-Headed Fusion Proteins Promote Subcutaneous Administration of Rapamycin to Breast Cancer In Vivo

Dhandhukia¹,

Li²,

Peddi³

et al. 2017

Theranostics

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Recombinant Elastin-Like Polypeptides (ELPs) serve as attractive scaffolds for nanoformulations because they can be charge-neutral, water soluble, high molecular weight, monodisperse, biodegradable, and decorated with functional proteins. We recently reported that fusion of the FK-506 binding protein 12 (FKBP) to an ELP nanoparticle (FSI) reduces rapamycin (Rapa) toxicity and enables intravenous (IV) therapy in both a xenograft breast cancer model and a murine autoimmune disease model. Rapa has poor solubility, which leads to variable oral bioavailability or drug precipitation following parenteral administration. While IV administration is routine during chemotherapy, cytostatic molecules like Rapa would require repeat administrations in clinical settings. To optimize FKBP/Rapa for subcutaneous (SC) administration, this manuscript expands upon first-generation FSI nanoparticles (Rh~ 25 nm) and compares them with two second-generation carriers (FA and FAF) that: i) do not self-assemble; ii) retain a hydrodynamic radius (Rh ~ 7 nm) above the renal filtration cutoff; iii) increase tumor accumulation; and iv) have either one (FA) or two (FAF) drug-binding FKBP domains per ELP protein.Methods: The carriers were compared and evaluated for temperature-concentration phase behavior by UV-Vis spectrophotometry; equilibrium binding and thermodynamics by Isothermal Titration Calorimetry; drug retention and formulation stability by Dialysis and Dynamic Light Scattering; in vitro efficacy using a cell proliferation assay; in vivo efficacy in human MDA-MB-468 orthotopic breast cancer xenografts; downstream target inhibition using western blot; tissue histopathology; and bio-distribution via optical imaging in the orthotopic xenograft mouse model.Results: Named after the two-headed bird in Hindu mythology, the 'Berunda polypeptide' FAF with molecular weight of 97 kDa and particle size, Rh ~ 7 nm demonstrated polypeptide conformation of a soluble hydrated coiled polymer, retained formulation stability for one month post Rapa loading, eliminated toxicity observed with free Rapa after SC administration, suppressed tumor growth, decreased phosphorylation of a downstream target, and increased tumor accumulation in orthotopic breast tumor xenografts.Conclusion: This comprehensive manuscript demonstrates the versatility of recombinant protein-polymers to investigate drug carrier architectures. Furthermore, their facilitation of SC administration of poorly soluble drugs, like Rapa, may enable chronic self-administration in patients.

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A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Cited by 21 publications

References 54 publications

A novel spheroid-based co-culture model mimics loss of keratinocyte differentiation, melanoma cell invasion, and drug-induced selection of ABCB5-expressing cells

A novel spheroid-based co-culture model mimics loss of keratinocyte differentiation, melanoma cell invasion, and drug-induced selection of ABCB5-expressing cells

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

Berunda Polypeptides: Multi-Headed Fusion Proteins Promote Subcutaneous Administration of Rapamycin to Breast Cancer In Vivo

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